The need for a safe and effective HIV vaccine is undisputed. In 2011 alone, nearly 2 million people died from AIDS related causes, while 2.5 million people were newly infected with HIV. Traditional approaches have failed to produce an efficacious HIV vaccine, and near-term prospects for a vaccine remain uncertain. We have taken a different approach to HIV immunoprophylaxis that completely bypasses the adaptive immune response. One selects an antibody (or antibody-like molecule) with the desired neutralizing properties, clones the antibody gene, and then inserts it into a recombinant adeno-associated virus (rAAV) vector. When injected (intramuscularly) into a host, the vector directs in vivo production of the antibody that leads to serum neutralizing activity against HIV. In other words, antibodies are produced by myofibers instead of plasma cells. In the proposed research, we will extend our previous work by constructing rAAV vectors using a new set of recently discovered human monoclonal antibodies with broad and potent activity against HIV. Such antibodies are ideal candidates because they have the potential to neutralize a wide range of HIV isolates at very achievable concentrations (Aim 1a). In the same vein, we will generate new forms of antibody-like molecules based on CD4-IgG fusion proteins designed to inhibit HIV entry, and test these in rAAV vectors and animal models (Aim 1b). In a separate project (Aim 2), we will develop a novel class of HIV entry inhibitors based on albumin fusion proteins, and likewise, test these in rAAV vectors and animal models. Finally, we will exploit a recently described inducible caspase system to develop a safety switch that will kill transduced cells, thereby eliminating transgene expression for rare situations where unexpected effects are observed (Aim 3).